ZIC SC 006743 (ZIC) | |||
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Title | Signal Transduction Events and the Regulation of Cell Growth | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Trepel, Jane | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $596,457 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Interferon (1.0%) Metastasis (45.0%) |
Breast (15.0%) Kidney Disease (15.0%) Leukemia (10.0%) Lung (30.0%) Prostate (30.0%) Urinary System (15.0%) Kidney Cancer (15.0%) |
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Research Type | |||
Technology Development and/or Marker Discovery Systemic Therapies - Discovery and Development |
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Abstract | |||
This project is designed to develop new approaches to cancer treatment through the study of growth, survival, and metastasis regulatory signal transduction events that identify molecular targets for anticancer drug development. Our work encompasses preclinical and clinical translational research through the translational drug development facility that I have established. Our work is currently focused on development and implementation of pharmacodynamic assays for targeted therapy trials, including assays for response to antiangiogenics, histone deacetylase inhibitors, Hsp90 inhibitors, immune-targeting agents, and detection of circulating epithelial tumor cells (CTCs) pre- and post-drug therapy, and, in collaboration with Dr. Peter Pinto of the Urologic Oncology Branch, CTC assays pre- and post-surgery. (1) Prostate cancer is the most common malignancy and second leading cause of cancer-related death in men in the United States. Androgen deprivation is the mainstay of treatment for men with metastatic prostate cancer, but most men treated with hormonal therapy will progress to a castrate-resistant state (CRPC). Once CRPC develops, treatment options are limited and median overall survival is currently approximately 32 months. Clearly a new therapeutic approach is needed for the treatment of CRPC. Once thought to reflect an androgen-independent state, it is now appreciated that CRPC is driven by androgen receptor (AR) signaling, and that more effective blockade of this pathway would be of enormous value in improving the efficacy of CRCP therapy. We have performed high-throughput screens and structure-activity relationship analyses (SAR), and have developed several novel antiandrogens for which the NIH has filed for intellectual property protection. In the first project we worked in collaboration with a number of labs including Len Neckers of the Urologic Oncology Branch, NCI and Marc Cox of the University of Texas, El Paso. We contributed to the SAR by identifying the most potent compound, and we performed all of the AR-driven gene expression studies. This project identified the mechanism of action of the active molecule as targeting the Hsp90-AR-FKBP52 complex by binding to the Hsp90-FKBP52 interface. As a result of this binding Hsp90 does not release AR in response to androgen binding. Thus AR does not enter the nucleus and AR signaling is inhibited. We published a report on this work in PNAS and NIH filed for patent on the compound. As a result of an SAR on a different chemical library we have identified a new antiandrogen with a novel chemical scaffold and a unique mechanism of action. Compound syntheses were guided by the results of our gene expression analyses, and performed by Sanjay Malhotra and Vineet Kumar of the NCI-Frederick Laboratory of Synthetic Chemistry. My laboratory is working on elucidating the mechanism of action of compounds with this scaffold, and NIH has filed a second antiandrogen patent for these compounds. Our data thus far demonstrate that these compounds have the unique ability to cause degradation of Hsp90 clients, including AR, without binding to either the N-terminal or C-terminal of Hsp90 itself. These compounds have the ability to cause degradation of AR splice variants characteristic of CRPC and are cytotoxic to CRPC cells driven by ligand binding domain (LBD) mutant AR and splice variant AR. In addition, we performed SAR studies on a novel series of dihydropyridones and identified an antiandrogen with potency comparable to enzalutamide (J Med Chem 56:8280-8297, 2014). (2) Our group has been working with intramural, extramural and industry investigators on a range of phase I, phase II and phase III clinical trials. I am an Associate Investigator on 67 clinical trials either open to accrual or open for analysis this year. For each of these trials we work with the PI to develop novel pharmacodynamic endpoints, including analysis of circulating endothelial progenitor cells, mature endothelial cell |